ES2894836T3 - Fluorinated CBD compounds, compositions and uses thereof - Google Patents

Abstract

A compound having a formula selected from any of: (a) **(See formula)** and (b) **(See formula)**

Description

DESCRIPTION

Fluorinated CBD compounds, compositions and uses thereof

TECHNOLOGICAL FIELD

The present invention relates to fluorine-substituted CBD compounds, compositions thereof and uses thereof for the preparation of medicaments.

PREVIOUS TECHNIQUE

Listed below are the references that are considered relevant as background to the subject matter described:

Bibliography

- Campos, A.C. and Guimaraes, F. S. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl). 199(2):223-30, 2008.

- File, S. E. Behavioral detection of anxiolytic action, in Experimental approaches to anxiety and depression (Elliott, J. M., Heal, D. J., and Marsden, C. A., eds.) pp. 25-44, Wiley, New York, 1992.

-Issy A. C., Salum C. and Del Bel E. A. Nitric oxide modulation of methylphenidate-induced disruption of prepulse inhibition in Swiss mice. Behavioral Brain Research. 205(2):475-81, 2009.

- Long, L. E., Malone, D. T., and Taylor D. A. Cannabidiol Reverses MK-801-Induced Disruption of Prepulse Inhibition in Mice. Neuropsychopharmacology 31:795-803, 2006.

- Moreira, F. A. and Guimaraes, F. S. Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. European Journal of Pharmacology. 512(2-3):199-205, 2005.

- Onaivi, E. S., Green, M. R., and Martin B. R. Pharmacological characterization of cannabinoids in the levated plus maze. Journal of Pharmacology and Experimental Therapeutics 255:1002-9, 1990.

- Paxinos G. and Watson C. The rat brain in stereotaxic coordinates. Academic Press, New York, 1997.

- Zanelati, T. V., Biojone, C., Moreira, F. A., Guimaraes, F. S. and Joca, S. R. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. British Journal of Pharmacology 159:122-8, 2010.

Acknowledgment of the foregoing references should not be construed to imply that they are in any way relevant to the patentability of the subject matter described herein. In addition, the following documents are identified:

Patent document WO2011/006099 which, on pages 27, 79 and 81, describes two fluorinated CBD-type compounds similar to the general structure (I) shown below, with a fluorine attached to the ortho or para position of the phenyl group.

Patent documents WO 2009/018389, US2011/052694 and WO2012/011112, which describe CBD derivatives similar to the general structure (I) shown below, but without fluorine substituents.

GENERAL DESCRIPTION

This invention describes a compound having the general formula (I):

where

--------- is a single or double bond;

Ri is selected from C1-C8 straight or branched alkyl, C2-C10 straight or branched alkenyl, C2-C10 straight or branched alkynyl, -C(=O)R8, -C(=O)OR9, each optionally substituted by at least one F;

R2 is selected from linear or branched C1-C8 alkyl, linear or branched C2-C10 alkenyl, and linear or branched C2-C10 alkynyl, each optionally substituted by at least one F;

R3 and R4 are each independently selected from H, straight or branched C1-C5 alkyl, -OR10, -C(=O)Rn and -OC(=O)R12; provided that at least one of R3 and R4 is other than H;

R5 is selected from C6-C12 straight or branched alkyl, C5-C9 straight or branched alkoxy, C1-C7 straight or branched ether, each being optionally substituted by at least one substituent selected from -OH, -NH3 , C1-C5 linear or branched amine, halogen, phenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

R8 and R9 are independently selected from H, OH, straight or branched C1-C5 alkyl, straight or branched C1-C5 alkoxy, -NH3, straight or branched C1-C5 amine;

R10 is selected from H, straight or branched C1-C5 alkyl; and

R11 and R12 are independently selected from H, OH, straight or branched C1-C5 alkyl, straight or branched C1-C5 alkoxy, -NH3, and straight or branched C1-C5 amine;

R 13 , R 14 , R 15 and R 16 are each optionally selected from H and F;

provided that at least one of R 13 , R 14 , R 15 and R 16 is F or at least one of R i and R 2 is substituted with F.

A compound having the general formula (II) is also disclosed:

where

--------- is a single or double bond;

Ri is selected from C1-C8 straight or branched alkyl, C2-C10 straight or branched alkenyl, C2-C10 straight or branched alkynyl, -C(=O)R8, -C(=O)OR9, each optionally substituted by at least one F;

R3 and R4 are each independently selected from H, straight or branched C1-C5 alkyl, -OR10, -C(=O)Rn and -OC(=O)R12; provided that at least one of R3 and R4 is other than H;

R5 is selected from C6-C12 straight or branched alkyl, C5-C9 straight or branched alkoxy, C1-C7 straight or branched ether, each being optionally substituted by at least one substituent selected from -OH, -NH3 , C1-C5 linear or branched amine, halogen, phenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

R8 and R9 are independently selected from H, OH, straight or branched C1-C5 alkyl, straight or branched C1-C5 alkoxy, -NH3, and straight or branched C1-C5 amine;

R10 is selected from H, straight or branched C1-C5 alkyl; and

R11 and R12 are independently selected from H, OH, straight or branched C1-C5 alkyl, straight or branched C1-C5 alkoxy, -NH3, and straight or branched C1-C5 amine;

R 13 , R 14 , R 15 , R 16 and R 17 are each optionally selected from H and F;

provided that at least one of R 13 , R 14 , R 15 and R 16 is F or R i is substituted with F.

A compound having the general formula (III) is also disclosed:

where

--------- is a single or double bond;

Ri is selected from C1-C8 straight or branched alkyl, C2-C10 straight or branched alkenyl, C2-C10 straight or branched alkynyl, -C(=O)R8 and -C(=O)OR9;

R2 is selected from C1-C8 straight or branched alkyl, C2-C10 straight or branched alkenyl, and C2-C10 straight or branched alkynyl;

R3 and R4 are each independently selected from H, straight or branched C1-C5 alkyl, -OR10, -C(=O)Rn and -OC(=O)R12; provided that at least one of R3 and R4 is other than H;

R5 is selected from C6-C12 straight or branched alkyl, C5-C9 straight or branched alkoxy, C1-C7 straight or branched ether, each being optionally substituted by at least one substituent selected from -OH, -NH3 , C1-C5 linear or branched amine, halogen, phenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

R8 and R9 are independently selected from H, OH, straight or branched C1-C5 alkyl, straight or branched C1-C5 alkoxy, -NH3, and straight or branched C1-C5 amine;

R10 is selected from H, straight or branched C1-C5 alkyl; and

R11 and R12 are independently selected from H, OH, straight or branched C1-C5 alkyl, straight or branched C1-C5 alkoxy, -NH3, and straight or branched C1-C5 amine;

R13 and R14 are each optionally selected from H and F;

provided that at least one of R13 and R14 is F.

Also disclosed is a compound having the general formula (IV)

where

--------- is a single or double bond;

R1 is selected from C1-C8 straight or branched alkyl, C2-C10 straight or branched alkenyl, C2-C10 straight or branched alkynyl, -C(=O)R8, -C(=O)OR9, each optionally substituted by at least one F;

R2 is selected from linear or branched C1-C8 alkyl, linear or branched C2-C10 alkenyl, and linear or branched C2-C10 alkynyl, each optionally substituted by at least one F;

R3 and R4 are each independently selected from H, straight or branched C1-C5 alkyl, -OR10, -C(=O)Rn and -OC(=O)R12; provided that at least one of R3 and R4 is other than H;

R5 is selected from C6-C12 straight or branched alkyl, C5-C9 straight or branched alkoxy, C1-C7 straight or branched ether, each being optionally substituted by at least one substituent selected from -OH, -NH3 , C1-C5 linear or branched amine, halogen, phenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

R8 and R9 are independently selected from H, OH, straight or branched C1-C5 alkyl, straight or branched C1-C5 alkoxy, -NH3, and straight or branched C1-C5 amine;

Rio is selected from H, C1-C5 linear or branched alkyl; and

R11 and R12 are independently selected from H, OH, straight or branched C1-C5 alkyl, straight or branched C1-C5 alkoxy, -NH3, and straight or branched C1-C5 amine;

R 15 and R 16 are each optionally selected from H and F;

provided that at least one of R 15 and R 16 is F or at least one of R i and R 2 is substituted with F.

In some descriptions,----- is a double bond.

In some other descriptions, R1 is straight or branched C1-C8 alkyl; R3 and R4 are each, independently, -OR10 and R10 is selected from H and straight or branched C1-C5 alkyl.

In other descriptions, R1 is straight or branched C1-C8 alkyl, and R3 and R4 are OH.

In other descriptions, R3 and R4 are each independently selected from H, -OR10 and -OC(=O)R12; R10 is selected from H, straight or branched C1-C5 alkyl; and R12 is selected from H, OH, straight or branched C1-C5 alkyl, -NH3, and straight or branched C1-C5 amine.

In some descriptions, R5 is straight or branched C6-C12 alkyl.

In further descriptions, at least one of R 13 , R 14 , R 15 and R 16 is F.

In other descriptions, at least one of R13 and R14 is F.

In other descriptions, at least one of R15 and R16 is F.

In other descriptions, at least one of R1 and R2 is substituted with F.

In further descriptions, R1 is selected from C1-C8 straight or branched alkyl, C2-C10 straight or branched alkenyl, and C2-C10 straight or branched alkynyl, each being substituted by F.

In further descriptions, R2 is selected from C1-C8 alkyl, C2-C10 straight or branched alkenyl, and C2-C10 straight or branched alkynyl, each substituted by F.

In further descriptions, a compound is of the general formula (V):

where R1, R2, R3, R4 and R5 are as defined therein.

In other descriptions, a compound is of the general formula (VI):

where Ri, R3, R4, R5, R15 and R16 are as defined therein.

A compound having the general formula (I) is also described:

where

--------- is a double bond;

R1 is linear or branched C1-C8 alkyl optionally substituted by at least one F;

R2 is a linear or branched C2-C10 alkenyl optionally substituted by at least one F;

R3 and R4 are each independently selected from H, -OR10 and -OC(=O)R12, provided that at least one of R3 and R4 is other than H;

R5 is C6-C12 linear or branched alkyl optionally substituted by at least one substituent selected from -OH, -NH3, C1-C5 linear or branched amine, halogen, phenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; R10 is selected from H, straight or branched C1-C5 alkyl; and

R12 is selected from H, OH, straight or branched C1-C5 alkyl, straight or branched C1-C5 alkoxy, -NH3, straight or branched C1-C5 amine;

R 13 , R 14 , R 15 and R 16 are each optionally selected from H and F;

provided that at least one of R 13 , R 14 , R 15 and R 16 is F or at least one of R i and R 2 is substituted with F.

The present invention provides a compound having the formula:

Also disclosed is a compound having the formula:

Also disclosed is a compound having the formula:

The invention further provides a compound having the formula:

The term "straight or branched C iC s alkyl" should be understood to encompass a straight or branched hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, where all bonds are single bonds. .

The term "C2-C10 straight or branched alkenyl" should be understood to encompass a straight or branched hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, having at least one unsaturated double bond between at least two carbon atoms.

The term "C2-C10 straight or branched alkynyl" should be understood to encompass a straight or branched hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, having at least one unsaturated triple bond between at least two carbon atoms.

It should be understood that the term "each optionally substituted by at least one F" refers to the option of having at least one fluorine atom substituted in any of the substituents such as R1 and/or R2 in any position, substituting at least one hydrogen atom.

The term "straight or branched C5-C9 alkoxy group" should be understood to encompass a radical of -OR where R is a straight or branched alkyl having 5, 6, 7, 8 or 9 carbon atoms.

The term "C1-C7 straight or branched ether" should be understood to encompass a radical of -R'OR where R is a straight or branched alkyl group having 1, 2, 3, 4, 5, 6 or 7 carbon atoms and R' is a linear or branched alkanyl group having 1, 2, 3, 4, 5, 6 or 7 carbon atoms.

The term "C1-C5 linear or branched amine" should be understood to encompass a primary (-NH2R), secondary (-NHRR') or tertiary (-N+RR'R") amine where R, R' and R" are each one independently a linear or branched alkyl group having 1, 2, 3, 4 or 5 carbon atoms.

The term "halogen" should be understood to encompass any halogen atom, including F, Cl, Br and I.

The term "aryl" is intended to encompass monocyclic or multicyclic aromatic groups containing from 6 to 19 carbon atoms. Aryl groups include, but are not limited to, groups such as substituted or unsubstituted fluorenyl, substituted or unsubstituted phenyl, and substituted or unsubstituted naphthyl.

In certain embodiments, the term "heteroaryl" refers to a monocyclic or multicyclic aromatic ring system of about 5 to about 15 members, where one or more (and in some embodiments between 1 and 3) of the ring system atoms is a heteroatom, ie, an element other than carbon including, but not limited to, nitrogen, oxygen, or sulfur. The heteroaryl group may optionally be fused with a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolinyl, and isoquinolinyl.

The term "cycloalkyl" refers to a non-aromatic monocyclic or multicyclic ring system, in one embodiment from 3 to 10 members, in another embodiment from 4 to 7 members, and in further embodiments from 5 to 6 member carbon atoms.

The term "heterocycloalkyl" refers to a non-aromatic monocyclic or multicyclic ring system, in one embodiment from 3 to 10 members, in another embodiment from 4 to 7 members, in a further embodiment from 5 to 6 members, where one or more (and in certain embodiments between 1 to 3) of the atoms in the ring system is a heteroatom, ie, an element other than carbon including, but not limited to, nitrogen, oxygen, or sulfur. In embodiments where the heteroatom(s) is(are) nitrogen, the nitrogen is optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclalkyl, acyl, guanidine, or the nitrogen may be a quaternary ammonium group where the substituents are selected as above.

When referring to a compound described in this invention, where at least one of R13, R14, R15 and R16 is F or at least one of R1 and R2 is substituted with F, it should be understood that it covers a compound where at least one of R13, R14, R15 and R16 is F or at least one of R1 and R2 is a substituent as previously defined in this invention, where at least one of its hydrogen atoms (anywhere in the portion) is replaced by a F atom.

In some other descriptions, at least one of R13, R14, R15 and R16 is F and at least one of R1 and R2 is substituted with F. According to this description, it is a compound where at least one of R13, R14 , R15 and R16 is F or at least one of R1 and R2 is a substituent as defined above in this invention, where at least one of its hydrogen atoms (anywhere in the moiety) is substituted by an F atom .

In another of its aspects, the invention provides a composition comprising at least one compound of the invention, as described hereinabove in all aspects and embodiments of a compound of the invention.

In some embodiments of a composition of the invention, said composition is a pharmaceutical composition.

A pharmaceutical composition of the present invention has potent antioxidant and/or free radical scavenging properties that prevent or reduce oxidative damage to biological systems, such as occurs in ischemic or reperfusion injury, or in neurodegenerative diseases. chronic diseases such as Alzheimer's disease, dementia caused by HIV, and many other diseases related to oxidation.

Thus, the invention provides a composition comprising a compound of the invention (as defined in any aspect and embodiment of a compound of the invention) that is an antioxidant composition. As used herein, an "antioxidant" is a substance that, when present in a mixture containing an oxidizable biological substrate molecule, significantly delays or prevents oxidation of the biological substrate molecule. Antioxidants can act by scavenging biologically important reactive free radicals or other reactive oxygen species (O2-, H2O2, OH, HOCl, feryl, peroxyl, peroxynitrite, and alkoxyl), or by preventing their formation, or by catalytically converting the free radical or other reactive species. of oxygen into a less reactive species.

Relative antioxidant activity can be measured by cyclic voltammetry studies, where voltage (x-axis) is an index of relative antioxidant activity. The voltage at which the first peak occurs is an indication of the voltage at which an electron is donated, which in turn is an index of antioxidant activity.

"Therapeutically effective antioxidant doses" can be determined by a number of approaches, including generating an empirical dose-response curve, predicting the potency and efficacy of a congener using quantitative structure-activity relationship (QSAR) or modeling approaches. molecular, and other procedures used in the pharmaceutical sciences. Since oxidative damage is generally cumulative, there is no minimum threshold (or dose) regarding efficacy. However, minimum doses can be established to produce a detectable therapeutic or prophylactic effect for given degrees of disease activity.

The present invention also relates to pharmaceutical compositions comprising at least one compound of the subject invention in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. Auxiliary agents are "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal, and sublingual administration), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal administration), or via an implant. The compositions can be prepared by any method known in the art of pharmacy.

Such procedures include the step of bringing into association the compounds used in the invention or combinations thereof with any auxiliary agents. Auxiliary agent(s), also called accessory ingredient(s), include(s) those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants , colorants, flavoring agents, antioxidants and wetting agents.

Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets, dragees or capsules, or as a powder or granules, or as a solution or suspension. The active ingredient can also be presented as a bolus or paste. The compositions can be further processed into a suppository or enema for rectal administration.

The invention further includes a pharmaceutical composition, as described above, in combination with packaging material, including instructions for use of the composition for use as described above.

For parenteral administration, suitable compositions include aqueous and non-aqueous sterile injection. The compositions may be presented in single-dose or multi-dose containers, eg, sealed vials and ampoules, and may be stored in a lyophilized (lyophilized) condition requiring only the addition of sterile liquid carrier, eg, water, prior to use. . For transdermal administration, for example, gels, patches or sprays may be contemplated. Compositions or formulations suitable for administration by the pulmonary route, eg, by nasal inhalation, include dusts or mists which may be generated by means of pressurized metered dose aerosols, nebulizers, or insufflators.

The exact dose and schedule of administration of the composition will necessarily depend on the therapeutic or nutritional effect that is to be achieved and may vary with the specific formulation, route of administration, age and condition of the subject to whom the composition is to be administered. .

In another of its aspects, the invention provides a compound of the invention, as described hereinabove in all aspects and embodiments of a compound of the invention, for use in the treatment of at least one condition, disease or disorder selected from the group consisting of: - psychiatric disorders (non-limiting examples include: anxiety and stress, depression, schizophrenia, panic, cannabis and tobacco addiction withdrawal symptoms, reward-facilitating effect of morphine and cocaine, reduces the effects of cannabis and THC such as memory loss, psychotic-like symptoms);

- inflammation (non-limiting examples include: Crohn's disease, inflammatory bowel disease, colitis, pancreatitis, asthma, chronic inflammatory and neuropathic pain);

- oxidation-related diseases, conditions or disorders (pathological conditions resulting, at least in part, from the production of or exposure to free radicals, in particular oxyradicals, or reactive oxygen species). It is apparent to those skilled in the art that most disease conditions are multifactorial, and that assigning or identifying the predominant causal factors for any particular condition is often difficult. For these reasons, the term "free radical-related disease" encompasses disease states that are recognized as conditions in which free radicals or reactive oxygen species (ROS) contribute to the pathology of the disease, or where it has been shown that administration of a free radical inhibitor (eg, deferoxamine), scavenger (eg, tocopherol, glutathione), or catalyst (eg, superoxide dismutase, catalase) produces a detectable benefit by decreasing symptoms, increasing survival, or provide other detectable clinical benefits by treating or preventing the disease state. Oxidation-associated diseases include, without limitation, free radical-related diseases such as ischemia, reperfusion injury, inflammatory diseases, systemic lupus erythematosus, myocardial ischemia or infarction, cerebrovascular accidents (such as thromboembolic or hemorrhagic stroke ) that can lead to ischemia or infarction in the brain, operative ischemia, traumatic hemorrhage (eg, hypovolemic shock that can lead to CNS hypoxia or anoxia), spinal cord trauma, Down syndrome, Crohn's disease, autoimmune diseases (eg, rheumatoid arthritis or diabetes), cataract formation, uveitis, emphysema, gastric ulcers, oxygen toxicity, neoplasia, unwanted apoptosis, radiation sickness, and others. The present invention is further directed to a compound or composition of the invention used in the treatment of oxidative diseases of the CNS. In some embodiments, the pharmaceutical composition of the present invention is used to prevent, arrest, or treat neurological damage in Parkinson's disease, Alzheimer's disease, and dementia caused by HIV; autoimmune neurodegeneration of the type that can occur in encephalitis, and hypoxic or anoxic neuronal damage that can result from apnea, respiratory arrest, or cardiac arrest, and anoxia caused by drowning, surgery, or brain trauma (such as concussion or spinal shock).

- rheumatoid arthritis;

- cardiovascular diseases (non-limiting examples include: reduce infarct size and increase blood flow in strokes; reduce vasoconstriction; decrease vascular damage caused by a high glucose environment; reduce vascular hyperpermeability);

- obesity (Non-limiting examples include: food consumption; decreased appetite); metabolic syndrome);

- diabetes, related disorders and symptoms (non-limiting examples include: type 1 and type 2, cardiomyopathy and retinopathy associated with diabetes);

- vomiting and nausea;

- ischemic injury or reperfusion injury related to the myocardium;

- liver or kidney diseases;

- hypoxic or ischemic injury;

- neuronal damage due to neurological disease or injury (non-limiting examples include: Parkinson's disease; Huntington's disease; Alzheimer's disease; cerebral infarction; hepatic encephalopathy; traumatic brain injury; cerebral ischemia; spinal cord injury; effects memory recovery);

- cancer and resistance to cancer chemotherapy (non-limiting examples include: cancer cell migration (metastasis); inhibits angiogenesis);

- epilepsy and seizures;

and any conditions or symptoms associated therewith.

In further embodiments, said inflammation-associated condition, disease, disorder or symptom is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, diabetes and any combination thereof.

In still other embodiments, said disease is a psychiatric disease or disorder or any symptom associated therewith.

In other embodiments, said psychiatric disease or disorder or any symptom associated therewith is selected from anxiety, stress, depression, schizophrenia, panic, withdrawal symptoms due to substance use, reward-facilitating effect of addictive substances, loss of memory and psychotic-like symptoms associated with substance abuse.

In another of its aspects, the invention provides a compound of the invention, as described hereinabove in all aspects and embodiments of a compound of the invention, for use in reducing oxidative stress.

When referring to "reduction of oxidative stress", it should be understood to encompass any qualitative or quantitative reduction of oxidative stress in a body tissue or cell of an individual treated with a compound or composition of the invention. Oxidative stress is characterized by an imbalance between the systemic manifestation of reactive oxygen species and the ability of a biological system to readily detoxify reactive intermediates or repair the resulting damage. Alterations in the normal oxidation-reduction state of cells can cause toxic effects through the production of peroxides and free radicals that damage all cell components, including proteins, lipids, and DNA. In addition, some reactive oxidative species act as cellular messengers in redox signaling. Therefore, oxidative stress can cause alterations in normal cell signaling mechanisms.

Among the non-limiting list of diseases, conditions or disorders related to oxidative stress in a cell or tissue of a subject are: cancer, Parkinson's disease, Alzheimer's disease, atherosclerosis, heart failure, myocardial infarction, schizophrenia, bipolar disorder , fragile X syndrome, sickle cell disease, lichen planus, vitiligo, autism, and chronic fatigue syndrome.

In a further aspect, the invention provides a compound of the invention, as described hereinabove in all aspects and embodiments of a compound of the invention, for use in the treatment of any disease, condition, or disorder caused by or associated with oxidative stress.

Oxidation-associated diseases include, without limitation, free radical-associated diseases such as ischemia, ischemic reperfusion injury, inflammatory diseases, systemic lupus erythematosus, myocardial ischemia or infarction, cerebrovascular accidents (such as thromboembolic stroke or hemorrhagic) that can lead to ischemia or infarction in the brain, operative ischemia, traumatic hemorrhage (for example, hypovolemic shock that can lead to hypoxia or anoxia of the CNS), spinal cord trauma, Down syndrome, Crohn's disease, autoimmune (eg, rheumatoid arthritis or diabetes), cataract formation, uveitis, emphysema, gastric ulcers, oxygen toxicity, neoplasia, unwanted apoptosis, radiation sickness, and others. The present invention is believed to be of particular benefit in the treatment of CNS oxidative diseases, due to the ability of cannabinoids to cross the blood-brain barrier and exert their antioxidant effects in the brain. In some embodiments, the pharmaceutical composition or compound of the present invention is used to prevent, arrest, or treat neurological damage in Parkinson's disease, Alzheimer's disease, and dementia caused by HIV; autoimmune neurodegeneration of the type that can occur in encephalitis, and hypoxic or anoxic neuronal damage that can result from apnea, respiratory arrest, or cardiac arrest, and anoxia caused by drowning, surgery, or brain trauma (such as concussion or spinal shock).

In some embodiments, said disease, condition or disorder caused by or associated with oxidative stress is selected from the group consisting of cancer, oxidative neurological disorders, free radical associated diseases, ischemia, ischemic reperfusion injury, inflammatory diseases, lupus erythematosus systemic, myocardial ischemia or infarction, cerebrovascular accidents, operative ischemia, traumatic hemorrhage, spinal cord trauma, Down syndrome, Crohn's disease, autoimmune diseases, cataract formation, uveitis, emphysema, gastric ulcers, oxygen toxicity, neoplasia , unwanted apoptosis, radiation sickness, and any combination thereof.

In a further aspect, the invention provides a compound as defined in all aspects and embodiments of a compound of the invention, for use in the treatment of CNS oxidative diseases, disorders or conditions.

In another aspect, the invention provides a compound as defined in all aspects and embodiments of a compound of the invention, for use in preventing, stopping or treating neurological damage in a subject suffering from at least one disease, disorder or condition selected from Parkinson's disease, Alzheimer's disease and dementia caused by HIV ; autoimmune neurodegeneration, hypoxic or anoxic neuronal damage, respiratory or cardiac arrest, anoxia caused by drowning and surgery or brain trauma, or any combination thereof.

In a further aspect, the invention provides a compound as defined in all aspects and embodiments of a compound of the invention, for use in the treatment of an ischemic or neurodegenerative disease of the central nervous system.

In some embodiments of a compound for the above use, said ischemic or neurodegenerative disease is selected from the group consisting of: ischemic infarction, Alzheimer's disease, Parkinson's disease and dementia caused by human immunodeficiency virus, Down syndrome , heart disease, or any combination thereof.

In a further aspect, the invention encompasses a use of a compound of the invention, as described hereinabove in all aspects and embodiments of a compound of the invention, for the manufacture of a medicament (or a pharmaceutical composition) .

The invention further provides a use of a compound of the invention, as described hereinabove in all aspects and embodiments of a compound of the invention, for the manufacture of a medicament for the treatment of at least one condition, disease or disorder selected from the group consisting of psychiatric disorders, inflammation, oxidation-associated conditions, rheumatoid arthritis, cardiovascular disease, obesity, diabetes and associated disorders and symptoms, vomiting and nausea, ischemic injury or reperfusion injury associated with cardiomyopathy, liver or kidney disease, hypoxic or ischemic injury, neuronal damage due to neurological disease or injury, cancer and resistance to cancer chemotherapy, epilepsy and seizures, and any conditions or symptoms associated therewith. In another aspect, the invention provides a use of a compound of the invention, as described hereinabove in all aspects and embodiments of a compound of the invention, for the manufacture of a medicament for stress reduction. oxidative.

In yet another aspect, the invention provides a use of a compound of the invention, as described hereinabove in all aspects and embodiments of a compound of the invention, for the manufacture of a medicament for the treatment of any disease, condition, or disorder caused by or associated with oxidative stress.

In some embodiments of a use mentioned above, said disease, condition or disorder caused by or associated with oxidative stress is selected from the group consisting of cancer, oxidative neurological disorders, free radical associated diseases, ischemia, ischemic reperfusion injury, inflammatory diseases, systemic lupus erythematosus, myocardial ischemia or infarction, cerebrovascular accidents, operative ischemia, traumatic hemorrhage, spinal cord trauma, Down syndrome, Crohn's disease, autoimmune diseases, cataract formation, uveitis, emphysema, gastric ulcers, oxygen toxicity, neoplasia, unwanted apoptosis, radiation sickness, and any combination thereof.

In a further aspect, the invention provides a use of a compound according to the invention (as defined in any of the aspects and embodiments of a compound of the invention), for the manufacture of a medicament for the treatment of diseases, disorders or CNS conditions associated with oxidation.

In another aspect, the invention provides a use of a compound according to the invention (as defined in any of the aspects and embodiments of a compound of the invention), for the manufacture of a medicament for preventing, impeding, stopping or treating neurological damage in a subject suffering from at least one disease, disorder or condition selected from Parkinson's disease, Alzheimer's disease and dementia caused by HIV; autoimmune neurodegeneration, hypoxic or anoxic neuronal damage, respiratory or cardiac arrest, anoxia caused by drowning and surgery or brain trauma, or any combination thereof. In a further aspect, the invention provides a use of a compound according to the invention (as defined in any of the aspects and embodiments of a compound of the invention), for the manufacture of a medicament for the treatment of an ischemic disease. or neurodegenerative of the central nervous system. In some embodiments of a prior use, said ischemic or neurodegenerative disease is selected from the group consisting of: ischemic infarction, Alzheimer's disease, Parkinson's disease and dementia caused by human immunodeficiency virus, Down syndrome, heart disease or any combination of them.

Also described is a method of treating an inflammation-associated condition, disease, disorder, or symptom in an individual in need thereof, said method comprising administering to said individual an effective amount of at least one compound of the invention, as described above. described hereinabove in all aspects and embodiments of a compound of the invention.

A method of reducing oxidative stress in a tissue or an organ of a subject in need thereof is also described, said method comprising administering to said individual an effective amount of at least one compound of the invention, as described above in this invention in all aspects and embodiments of a compound of the invention.

Also described is a method of treating any disease, condition or disorder related to oxidative stress in an individual in need thereof, said method comprising administering to said individual an effective amount of at least one compound of the invention, as described above. defined above in this invention in all aspects and embodiments of a compound of the invention.

In some descriptions of a prior method, said disease, condition or disorder caused by or associated with oxidative stress is selected from the group consisting of cancer, oxidative neurological disorders, free radical associated diseases, ischemia, ischemic reperfusion injury, inflammatory diseases, systemic lupus erythematosus, myocardial ischemia or infarction, cerebrovascular accidents, operative ischemia, traumatic hemorrhage, spinal cord trauma, Down syndrome, Crohn's disease, autoimmune diseases, cataract formation, uveitis, emphysema, gastric ulcers, oxygen toxicity, neoplasia, unwanted apoptosis, radiation sickness, and any combination thereof.

Also disclosed is a method of treating an oxidation-associated CNS disease, disorder, or condition in an individual, comprising administering to said individual a therapeutically effective amount of a compound of the invention (as defined in any of aspects and embodiments of a compound of the invention).

Also described is a method of preventing, arresting, or treating neurological damage in an individual suffering from at least one disease, disorder, or condition selected from Parkinson's disease, Alzheimer's disease, and dementia caused by HIV; autoimmune neurodegeneration, hypoxic or anoxic neuronal damage, respiratory or cardiac arrest, anoxia caused by drowning and surgery or brain trauma, comprising administering to said individual a therapeutically effective amount of a compound of the invention (as defined in any of the aspects and embodiments of a compound of the invention). Also described is a method of treating an ischemic or neurodegenerative disease in the central nervous system of an individual, comprising administering to the individual a therapeutically effective amount of a compound of the invention (as defined in any of the aspects and embodiments of a compound of the invention).

In some descriptions of a prior method, said ischemic or neurodegenerative disease is selected from the group consisting of: an ischemic infarction, Alzheimer's disease, Parkinson's disease and dementia caused by human immunodeficiency virus, Down's syndrome, heart disease or any combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to better understand the subject matter described in this invention and to exemplify how it can be carried out in practice, embodiments are described below by way of non-limiting example only, with reference to the accompanying drawings, in which:

Figure 1 shows the effects of HU-475 (a compound of the invention 1, 3 and 10 nmol, n=8-9 animals/group) and vehicle (n=7) microinjected into the dorsolateral periaqueductal gray matter of rats subjected to to the elevated cross labyrinth. Data expressed as mean ± SEM of the percentage of entries in the open arms. * indicates a significant difference from vehicle (p<0.05).

Figure 2 shows the effects of HU-475 (a compound of the invention 1, 3 and 10 nmol, n=8-9 animals/group) and vehicle inputs (n=7) microinjected into the dorsolateral periaqueductal gray matter of rats submitted to the raised cross maze. Data expressed as means ± SEM of the percentage of time spent in the open arms. indicates a trend (p<0.1) for a difference from vehicle.

Figure 3 shows the effects of HU-474 (a compound of the invention 1, 3 and 10 mg/kg, n=6-8 animals/group) and vehicle (n=7) in mice subjected to the elevated plus maze. . Data expressed as mean ± SEM of the percentage of time in the open arms. * indicates a significant difference from the vehicle.

Figure 4 shows the effects of HU-474 (a compound of the invention 1, 3 and 10 mg/kg, n=6-8 animals/group) and vehicle (n=7) in mice subjected to the elevated plus maze. . Data expressed as mean ± SEM of the percentage of entries in the open arms.

Figure 5 shows the effects of HU-474 (a compound of the invention 1, 3 and 10 mg/kg, n=6-8 animals/group) and vehicle (n=7) on the immobility time of mice. (s) displayed by the mice subjected to the FST test. Data expressed as mean ± SEM. * indicates a significant difference from the vehicle.

Figure 6 shows the effects of HU-474 (3 and 10 mg/kg intraperitoneally) in mice on the impairment of IEP induced by MK-801 (M 0.5 mg/kg). Results are expressed as means ± SEM. * indicates a significant difference from the vehicle-vehicle group, # indicates a significant difference from the vehicle-MK group.

DETAILED DESCRIPTION

Example 1: fluorination of cannabidiol (HU-474)

To a solution of cannabidiol (942 mg, 3 mmol) in dry CH2Cl2 (42 mL) was added 1-fluoropyridinium triflate (742 mg, 3 mmol), and the reaction mixture was stirred at room temperature overnight. After diluting with CH2Cl2, the mixture was washed with saturated aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4 and evaporated. The obtained oil was chromatographed on a column of silica gel (75 g). Elution with 2% ether in petroleum ether gave the compound 4'-fluoro-cannabidiol (HU-474) as a solid (300 mg, 27%), m.p. 59 to 61°C. 1 H NMR (300 MHz, CDCla) 86.17 (1H, s, arom.) 5.52 (1H, s), 4.56 (1H, s), 4.44 (1H, s), 3.92 ( 1H, s), 2.50 (2H, b), 2.19-2.05 (2H, b), 1.77 (3H, s), 0.86 (3H, t). MS, m/e = 332 (M+).

Comparative example 2: fluorination of cannabidiol diacetate (HU-475) Step A

10-hydroxy-cannabidiol diacetate

To a suspension of SeO2 (219 mg, 2 mmol) and t-BuOOH (2.8 mL, 70% in water) in CH2Cl2 (7 mL) was added a solution of cannabidiol diacetate (2 g, 5 mmol) in CH2Cl2 (10ml). After stirring the mixture at room temperature overnight, it was washed with saturated aqueous NaHCO3 solution followed by saturated NaHSO3 solution. The organic layer was separated, dried over MgSO4, filtered and evaporated. The oil obtained was purified on a silica gel column (50 g). Elution with 13% ether in petroleum ether afforded the required compound, 10-hydroxy-cannabidiol diacetate (670 mg, 40%) as an oil. 1H NMR (300 MHz, CDCla), 86.7 (2H, s), 5.17 (1H, s), 4.99 (1H, s), 4.87 (1H, s), 3.70-3 .80 (2H m), 3.53-3.58 (1H, m), 2.52-2.57 (2H, t J = 7.6 Hz), 2.39-2.48 (1H d J = 5.1 Hz), 2.18 (6H, s), 2.06 (1H, s), 2.0 (1H, s), 1.58 (1H, s), 1.25-1.31 (4H, m), 0.86-0.90 (3H t, J = 6.45 Hz).

Stage B

The alcohol (414 mg, 1 mmol) in dry CH2Cl2 (4 mL) was added under N2 to an ice-cold solution of DAST (0.18 mL, 1.5 mmol). After 15 min. at 0 °C, solid Na2CÜ3 (125 mg, 1 mmol) was added. The organic phase was then washed twice with a cold 1M Na2C03 aqueous solution, and then with water. The organic layer was separated, dried over MgSÜ4, filtered and evaporated. The resulting crude material was purified on a silica gel column (20 g) using 10% ether in petroleum ether to give the fluorinated product 10-fluoro-cannabidiol diacetate (HU-475) (77.5 mg, 18 .6%). 1H NMR (300 MHz, CDCh), 56.74 (2H, s), 5.21 (1H, s), 5.01 (1H, s), 4.87 (1H, s), 4.60 (1H , s), 4.50 (1H, s), 3.6 (1H, b), 2.73 (1H, t), 2.57 (2H, t), 2.21 (6H, s), 2 0.08-1.59 (8H, ms), 1.32 (3H, s), 0.90 (3H, t). MS, m/e = 416 (M+).

Example 3: In vivo effect of HU-474 in mice and HU-475 in rats

1. Animals

Male Wistar rats (220-250 g) and Swiss mice (25-30 g) from the Central Animal Farm of the Ribeirao Preto School of Medicine (FMRP-USP) were kept in groups of five animals per box (41 x 33 x 17 cm) in a temperature-controlled room (24 ± 2 °C) with a light-dark cycle of 12 x 12 h. They received food and water ad libitum throughout the study period.

2. Compositions

HU-474 (1, 3, and 10 mg/kg) was administered intraperitoneally (IP) to mice at a volume of 10 mL/kg, and HU-475 (1, 3, and 10 nmol) was injected through the substance. Dorsolateral periaqueductal gray (intra-dlPAG) in rats. Both drugs were dissolved in 2% Tween 80 in sterile saline.

3. Stereotaxic surgery ( HU-475)

Rats underwent stereotaxic surgery to unilaterally implant cannulae (9.0 mm, 0.6 mm outer diameter) into the dorsolateral periaqueductal gray matter (coordinates: lateral: -1.9 mm; depth: -4.3 mm). ; angle: 16° from lambda; Paxinos and Watson, 2005), fixed to the skull with acrylic cement (Campos & Guimaraes, 2008). The surgeries were performed under anesthesia with 2.5% tribromoethanol (10.0 ml/kg, by IP route) and immediately afterwards the animals received veterinary pentabiotic (0.2 ml, intramuscular) and analgesic (banamine, 1.0 ml). /kg, subcutaneous) to prevent infection and decrease post-surgical pain. After surgery, the animals underwent a recovery period of 5 to 7 days before behavioral tests.

4. Microinjection ( HU-475)

Animals received unilateral microinjections of vehicle or HU-475 into the dorsolateral periaqueductal gray matter prior to behavioral testing. For this, microneedles (10.0 mm, 0.3 mm outside diameter) were inserted into the guide cannulas, connected to a microsyringe (Hamilton, USA, 10 ml) through a polyethylene segment (P10). . The solutions were injected with the help of an infusion pump (KD Scientific, USA). A solution volume of 0.2 μl was injected over 1 minute. After the injections, the needles remained inserted in the cannulas for an additional 30 seconds to prevent drug reflux (Campos & Guimaraes, 2008).

5. Apparatus

5.1 Rats in elevated cross maze ( LCE)

The wooden LCE used to perform the experiments was located in a sound-attenuated, temperature-controlled room (23 °C), with an incandescent light (40 W) located 1.3 m away from the maze. The apparatus consists of two opposite open arms (50 x 10 cm) without side walls, perpendicular to two closed arms (50 x 10 x 40 cm), with a central platform common to all arms (10 x 10 cm). The apparatus is raised 50 cm from the ground and has an acrylic edge (1 cm) on the open arms to prevent animals from falling. In this model, rodents logically avoid the open arms, exploring the closed arms more widely. Anxiolytic drugs increase exploration in the open arms without affecting the number of entries in the closed arms, which is often used to assess overall exploratory activity (File, 1992). Ten minutes after the last injection, the animal was placed on the central platform of the maze with its head facing one of the closed arms. The test lasted 5 min and was recorded. Animal behavior was analyzed with the help of Anymaze software (version 4.5, Stoelting). This software indicates the location of the animal in the LCE and automatically calculates the percentage of entries (Peo), the time spent in the open arms (Pto) and the number of entries in the closed arms (EA). Animals were only considered to enter an open or closed arm when 90% of their body was within the region. All the experiments were carried out in the morning period (from 8 to 12 in the morning).

5.2 Mice in elevated cross maze ( LCE)

Similar to 5.1, except each arm measured 30 x 5 cm.

5.3 Mice subjected to the forced swim test ( PNF)

The animals were individually subjected to 6 minutes of forced swimming in glass cylinders (height 25 cm, diameter 17 cm) containing 10 cm of water. The mice were videotaped and the time of immobility (characterized by the slow movements necessary to avoid drowning) was measured during the last 4-minute period. The water was changed after each test to maintain the temperature at 23-25 °C and prevent the influence of the alarm substances (Zanelati et al., 2010).

6. Histology: rats

Following behavioral testing, animals were anesthetized with 4% chloral hydrate (10 mL/kg) and perfused with 0.9% saline. Brains were removed and kept in 10% formalin solution for 3-7 days. Shortly thereafter, the brains were cut into 50 µm thick sections on a cryostat (Cryocut 1800). Injection sites were identified on atlas diagrams by Paxinos and Watson (Paxinos and Watson, 2005). The rats that received injections outside the target area were included in a separate group (outgroup).

7. Statistical analysis

The results of the HU-475 and HU-474 tests in the elevated plus maze were analyzed by Kruskal-Wallis tests followed by Mann-Whitney tests. Data from animals tested in PNF were analyzed by one-way ANOVA followed by Duncan's test.

Results.

HU-475. The drug increased the percentage of entries (X2=9.66, DF=4, p<0.05, figure 1) and tended to do the same (X2=8.5, DF=4, p=0.075, figure 2 ) with the percentage of time spent in the open arms. No effect was found on the number of entries in the closed arms.

Figure 1 shows the effects of HU-475 (1, 3 and 10 nmol, n=8-9 animals/group) and vehicle (n=7) microinjected into the dorsolateral periaqueductal gray matter of rats subjected to the elevated cross maze. . The results of the animals that received the 3 nmol dose outside the target area are shown in the OUT group (n=6). Data expressed as mean ± SEM of the percentage of entries in the open arms. * indicates a significant difference from vehicle (p<0.05). Figure 2 shows the effects of HU-475 (1, 3 and 10 nmol, n=8-9 animals/group) and vehicle (n=7) microinjected into the dorsolateral periaqueductal gray matter of rats subjected to the elevated cross maze. . The results of the animals that received the 3 nmol dose outside the target area are shown in the OUT group. Data expressed as mean ± SEM of the percentage of time spent in the open arms. indicates a trend (p<0.1) for a difference from vehicle. HU-474. The drug increased the percentage of time spent in the open arms of the CSF (X2= 8.13, DF=3, p<0.05, Figure 3). No effect was found in the percentage of entries in these same arms (figure 4) or in the number of entries in closed arms. The drug also decreased PNF immobility time (F3,2=4.06, p=0.019, Figure 5) at the 3 m/kg dose. Doses of 1 and 10 mg/kg were ineffective. Figure 3 shows the effects of HU-474 (1, 3 and 10 mg/kg, n=6-8 animals/group) and vehicle (n=7) in mice subjected to the elevated plus maze. Data expressed as mean ± SEM of the percentage of time in the open arms. * indicates a significant difference from the vehicle. Figure 4 shows the effects of HU-474 (1, 3 and 10 mg/kg, n=6-8 animals/group) and vehicle (n=7) in mice subjected to the elevated plus maze. Data expressed as mean ± SEM of the percentage of entries in the open arms. Figure 5 shows the effects of HU-474 (1, 3 and 10 mg/kg, n=6-8 animals/group) and vehicle (n=7) on mice immobility time (s) shown by mice subjected to the FST test. Data expressed as mean ± SEM. * indicates a significant difference from the vehicle.

Analysis ( comparative results with CBD)

Injection of HU-475 into the dorsolateral periaqueductal gray matter increased exploration of the open arms of the ECL without changing the number of entries in the closed arms. This indicates an anxiolytic-like effect (File, 1991) and was similar to that produced by CBD using the same paradigm, including a bell-shaped dose-response curve. However, the effective dose of CBD was 30 nmol (doses tested: 15, 30 and 60 nmol), the same dose produced an anxiolytic-like effect in the Vogel punished licking test (Campos & Guimaraes, 2008). In this model, therefore, HU-475 was 10 times more potent than CBD.

Systemic administration of HU-474 induced anxiolytic-like effects in mice subjected to LCE tests with a characteristic bell-shaped dose-response curve. The effective dose was 3 mg/kg. Compared to CBD, Onaivi et al. (1990) observed, in a study carried out with a different strain of mice (ICR), similar anxiolytic effects at doses of 1 and 10 mg/kg intraperitoneally (with 10 mg/kg of CBD being more effective). HU-474 also reduced immobility time in mice subjected to the forced swim test, a model sensitive to antidepressant drugs. CBD also produced an antidepressant-like effect in Swiss mice subjected to this model at a dose of 30 mg/kg intraperitoneally (tested doses of 3, 10, 30, and 100 mg/kg). Therefore, in this model, HU-474 was 10 times more potent than CBD.

Example 4: Pre-stimulus inhibition test (HU-474)

1. Animals

The experiments were performed with male C57BL/6J mice weighing 25-30 g. The animals were maintained throughout the experimental period under standard laboratory conditions with free access to water and food.

2. Compositions

HU-474 (3 and 10 mg/kg) was dissolved in 2% Tween 80 in sterile saline (vehicle). MK-801 (an NMDA antagonist, 0.5 mg/kg, Sigma, USA) was dissolved in saline. Drugs were administered intraperitoneally (IP) at a volume of 10 ml/kg.

3. Experimental procedures

Animals (n=9-11/group) received the administration of vehicle or HU-474 (3 and 10 mg/kg) by the IP route followed, 30 minutes later, by saline or MK-801 (0.5 mg/kg). kg), giving rise to the following experimental groups: saline solution vehicle, HU 10 saline solution, MK-801 vehicle, HU 3 MK-801, HU 10 MK-801. The animals were subjected to the IEP test 20 minutes after the last injection of the drug.

4. Inhibition by previous stimulus ( IEP)

The IEP was carried out in three consecutive stages. The first consisted of an acclimatization period during which no stimulus was presented. In the second stage, called habituation, only the stimulus that triggers the startle (stimulus) was presented. The stage that evaluated the inhibition of the startle reflex consisted of 64 random presentations of the different stimuli: (i) stimulus (white noise) of 105 dB at 20 ms, (II) previous stimulus (pure tone frequency of 7 kHz) of 80, 85 and 90 dB at 10 ms, (III) followed by a pre-stimulus interval of 100 ms between them and (IV) zero (no stimulus). During this session, stimuli are presented at regular 30-s intervals, 8 presentations of each stimulus. The percentage of IEP was expressed as the percentage of inhibition of the startle amplitude in response to multiple presentations of the stimulus preceded by the previous stimulus (EP), as a function of the amplitude of the response only to the stimulus (E), which was obtained in the following formula % EP = 100 -((EP / E) x 100). Using this formula, 0% represents that there is no difference between the startle amplitude triggered by the stimulus alone or the stimulus preceded by the previous stimulus, and thus no inhibition of the previous stimulus. This transformation was performed to reduce statistical variability attributable to between-animal differences and represents a direct measure of prestimulus inhibition (Issy et al., 2009).

5. Statistical analysis

The IEP percentage was analyzed using repeated measures MANOVA with treatment as the independent factor and the intensity of the previous stimulus (80, 85 and 90 dB) as repeated measure. Duncan's post hoc test (P<0.05) was used to identify the differences revealed by the significant MANOVA.

Results

MANOVA revealed significant main effects of prestimulus (F2.70=23.53, P<0.05) and treatment (F4.35=45.42, P<0.05) intensity but no interaction between intensity of the previous stimulus and the treatment (F8,70=1.08, P>0.05). MK-801 promoted a significant alteration of IEP for all prestimulus intensities tested (P<0.05, Duncan posttest). HU-474 (10 mg/kg) attenuated IEP disturbance by MK-801 at all pre-stimulus intensities tested (P<0.05, Figure 6). Figure 6 shows the effects of HU-474 (3 and 10 mg/kg intraperitoneally) in mice on the impairment of IEP induced by MK-801 (M 0.5 mg/kg). The results show the percentage inhibition of startle amplitude in response to multiple presentations of the stimulus preceded by the previous stimulus and are expressed as means ± SEM. * indicates a significant difference from the vehicle-vehicle group, # indicates a significant difference from the vehicle-MK group.

Analysis (comparison with CBD results)

A single administration of CBD (5 mg/kg, intraperitoneally) attenuated IEP deficits caused by MK-801 (0.3-1 mg/kg, intraperitoneally) in Swiss mice (Long et al., 2006) . Note that, in this case, the effective dose of CBD (the authors also tested 1 and 15 mg/kg) was lower than that observed in HU-474 (10 mg/kg). The above experimental procedure is also carried out with a dose of 30 mg/kg of HU-474. E1HU-474 has also been tested in dopamine-based models (d-amphetamine-induced hyperlocomotion). Effective doses of CBD are 30 and 60 mg/kg (Swiss mice). The 30 mg/kg dose is capable of attenuating hyperlocomotion induced by MK801 (Moreira and Guimaraes, 2005).

Claims (7)

1. A compound having a formula selected from any of: (to)

and (b)

2. The compound of claim 1, having a formula of:

3. A composition comprising at least one compound according to claim 1 or 2. 4. A compound according to claim 1 or 2, or a composition according to claim 3, for use in the treatment of at least one condition, disease or disorder selected from the group consisting of psychiatric disorders, inflammation, conditions associated with oxidation, rheumatoid arthritis, cardiovascular disease, obesity, diabetes and associated disorders and symptoms, vomiting and nausea, ischemic injury or reperfusion injury associated with cardiomyopathy, liver or kidney disease, hypoxic or ischemic injury, neuronal damage due to disease or injury neurological, cancer and resistance to cancer chemotherapy, epilepsy and seizures, and any conditions or symptoms associated therewith. 5. A compound or composition for use according to claim 4, wherein said psychiatric condition or disorder or any symptom associated therewith is selected from anxiety, stress, depression, schizophrenia, panic, withdrawal symptoms due to substance use, effect facilitator of the reward of addictive substances, memory loss and psychotic-like symptoms associated with substance abuse. 6. A compound according to claim 1 or 2, or a composition according to claim 3, for use in the treatment of any disease, condition or disorder caused by or associated with oxidative stress. 7. A compound according to claim 1 or 2, or a composition according to claim 3, for use in preventing, arresting or treating neurological damage in a subject suffering from at least one disease, disorder or condition selected from the disease of Parkinson's, Alzheimer's disease and dementia caused by HIV; autoimmune neurodegeneration, hypoxic or anoxic neuronal damage, respiratory or cardiac arrest, anoxia caused by drowning and surgery or traumatic brain injury or any combination thereof. Ċ